The present invention relates to an efficient and general palladium-catalyzed, regioselective process for the preparation of a wide variety, of multifunctionally substituted aromatic heteroaryl-1-alkynes of the formula (I) starting from aromatic heteroaryl tosylates and terminal alkynes.
Heteroaryl-1-alkynes play an important role as key synthetic intermediates. The ability of the alkyne moiety of intermediates of the formula I to selectively react with various electrophiles or nucleophiles with or without catalytic assistance of acids or bases or transition metal is well known to those skilled in the art. Thus, heteroaryl-1-alkynes are valuable synthetic precursors for a wide variety of other compound classes, like for example heteroaromatic analogues of indoles, benzofuranes, benzothiophenes, isoquinolines, N-oxide isoquinolines, acetophenones, benzoic acids, heteroaryl-alkenyls, naphthalenes, cinnolines, chromenones and isocoumarins. In addition, heteroaryl-1-alkynes are well known as pharmaceutically active ingredients and several reports document the activity on a variety of biological targets, as well as the fact that several heteroaryl-1-alkynes are in development or are marketed as drugs (J B. G. Czito, T. J. Hong, D. P. Cohen, W. P. Petros, D. S. Tyler, T. N. Pappas, D. L. Yu, C. G. Lee, A. C. Lockhart, M. A. Morse, N. Fernando, H. I. Hurwitz, Cancer Invest. 2006, 24, 9-17; J. J. Reid, Curr. Opin. Invest. Drugs 2001, 2, 68-71, Y. Iso, E. Grajkowska, J. T. Wroblewski, J. Davis, N. E. Goeders, K. M. Johnson, S. Sanker, B. L. Roth, W. Tueckmantel, A. P. Kozikowski, J. Med. Chem. 2006, 49, 1080-1100.) The use of heteroaryl-1-alkynes is of course not limited to the above-mentioned pharmaceutical application. For example it is well known that heteroaryl-1-alkynes can be useful in agricultural applications like for example as herbicides, fungicides, nematicidals, parasiticides, insecticides, acaricides and arthropodicides. In addition they are used as diagnostic agents, liquid crystals and in polymers.
Among the synthetic repertoire for the preparation of heteroaryl-1-alkynes, the transition metal catalyzed formation of the C(sp)-C(sp2) bond between the heteroaryl and the alkyne moiety is by far the most commonly used strategy. For this purpose numerous transition metal catalyzed cross-coupling methodologies between a heteroaryl halide or heteroaryl triflate and an organometalic alkyne involving for example discrete zinc, tin, boron, copper, and silicon species have been developed. In contrast to these methods the palladium-catalyzed and optionally copper co-catalyzed cross-coupling of an heteroaryl halide or heteroaryl triflate and a non-metalated terminal alkyne as precursors (“Sonogashira coupling”) has turned out to be one of the most powerful and straightforward methods for the construction of heteroaryl-1-alkynes, since terminal alkynes can be used without prior transformation into an organometalic derivative.
Despite the large number of applications of the Sonogashira reaction, the coupling partners of the alkyne component are heteroaryl iodides, heteroaryl bromides and more recently also heteroaryl chlorides and heteroaryl triflates. All described Sonogashira couplings involving tosylates are limited to non-aromatic imino-tosylates or enol-tosylates (P. Jones et al. Tetrahedron 2002, 58, 9973-9981; X. Li et al. Org. Lett. 2005, 7, 4919-4922; J. Wu et al. J. Org. Chem. 2001, 66, 3642). A further Sonogashira coupling reaction with the non-aromatic 4-tosyl-6-methyl-2H-pyran-2-one catalyzed by a zeolite supported, heterogenous palladium-catalyst was disclosed by L. Djakovitch and P. Rollet (Adv. Synth. Catal.; 2004, 346, 1782-1792).
It has now been found that aromatic heteroaryl-1-alkynes of the formula I can be prepared using heteroaryl-tosylates. The object is achieved by a homogenous palladium catalyzed Sonogashira reaction using aromatic heteroaryl-tosylates and terminal alkynes in the presence of a base, a ligand and a protic solvent.
The use of heteroaryl tosylates or heteroaryl benzensulfonate derivatives offers various advantages over the use of heteroaryl triflates or heteroaryl nonaflates. They are easily prepared by reacting the corresponding phenol with Tos2O or TosCl, which are stable, inexpensive, and easy to handle solid reagents on large scale, in comparison to the highly reactive, moisture sensitive and expensive Tf2O or TfCl, required for the preparation of the heteroaryl triflates. Furthermore, the resulting heteroaryl tosylates are often highly crystalline solids simplifying subsequent purification procedures. Moreover heteroaryl tosylates are less reactive than heteroaryl triflates and are therefore less prone to unwanted hydrolytic cleavage by water or other protic solvents. The superior stability enables those substrates to remain unaffected by various reaction conditions allowing for example to introduce the tosylate group at an early stage of a synthesis and to carry the tosyl moiety unaffected through various other synthetic transformations and then finally to react the heteroaryl tosylate group in a Sonogashira cross coupling reaction.